1. Angela Stein, Pharm.D. PGY-1 Pharmacy Resident St. Johns Mercy Medical Center St. Louis College of Pharmacy

2. FDA Approved Indications Essential hypertension Non-FDA Approved Indications Attention deficit hyperactivity disorder Hot sweats Ischemic foot ulcer; Adjunct Nicotine dependence Opioid withdrawal Tic disorder

3.  Stimulates the presynaptic alpha-2 receptor in the brain and imidazoline receptor leading to inhibition of norepinephrine release  Inhibitory effects on NE release in the locus coeruleus

4.  Opioids activate opiate receptors in the locus coeruleus  ↓ adenylate cyclase → ↓ cAMP production  K+ efflux ↑, Calcium influx ↓ OVERALL RESULT= ↓ NE release

5.  NE release gradually ↑ to normal levels as tolerance develops  Once opioids is withdrawn, loss of inhibitory effect  increase in NE release to well above normal levels  Increase NE leads to withdrawal symptoms  Administration of opioids results in ↓ in neuronal activity and ↓ withdrawal symptoms

6.  Initial treatment of a neonate experiencing drug withdrawal should be supportive, since pharmacologic therapy prolongs hospitalization and subject the infant to exposure to drugs that may not be warrented  Supportive care: swaddeling, frequent small feedings of hypercaloric (24 cal.oz) formula o suppl additioanl caloric requirements, observation of sleeping patterns, temperature stability, weight gain or loss, or change in clinical status  Assess infants of drug abusing mothers includes Heatitis B and C and sexually transmitted diseases including HIV

7.  Clonidine Pharmacologic therapy  Effectively reduces withdrawal signs in adults  0.5-1 ug/kg in a single dose followed by a maintenance dose of 3 to 5 ug.kg/day, divided every 4 ti 6 hours  Blood levels 0.1-0.3 ng/ml  Poor sleep only sign that seems refractory  Length of therapy for infants treated with clonidine was significantly shorter when compared to phenobarbital (13 vs 27 days (P=0.05)  Larger controlled trials and pharmacokintic data is needed before clonidine can be avocated as routine treatment.

9.  Background: Treatment of NAS often prolongs hospitalization  Study Design: Prospective, block-randomized, double-blind, placebo-controlled trial  Outcomes: Total duration of pharmacotherapy for NAS Amount of DTO required to treat NAS Treatment failures Seizures weight gain Blood pressure, heart rate, hemoglobin saturation

10. Methods:  Treatment Clonidine 1 ug/kg every 4 hours+ diluted tincture of opium (DTO) 0.4 mg/ml DTO alone  Inclusion 0-14 days old Pernatal exposure to opioids Moderate to severe NAS  Exclusion Gestational age <35 weeks Intrauterine growth retardation (birth weight below 5 th percentile Congenital anomalies Illness requiring oxygen breastfeeding  3 baltimore hospitals  80 patients were eligible and randomized  0.2 ml DTO was started on all infants (0.08 mg ME) Q4H  Uncontrolled if 2 consecutive MFS > 9. DTO dose escalation to 0.3, 0.4, 0.5 ml every 4 hours then 0.5, 0.7,. 0.9 ml every 3 hours untill withdrawal syptoms were controlled (MFS < 9)  Once controlled, infants were maintained on that dose for 48 hours  DTO was de-escalated by 0.05 ml/dose for each 24 hour period  If 2 consecutive MFSs of >12 during de-escalatio., the last controlled dose was re-initiated  2 consecutive MFSs > 9 on the highest dose (0.9 ml Q3H were classified as treatment failures Total opioid dose, length of treatment, MFSs, and vital signs were collected Additioanl Assessments Temperature, heart rate, respiratory rate, oxygen saturation, blood pressure, MFSs scores every 3 to 4 hours Blood pressure every 4 hours for the first 48 hours and after stopping clonidine or placebo otherwise every 12 hours

11.  To demonstrate a 25% reduction in primary outcome, a power of 0.8 and a 2-sided alpha value of 0.05 were needed for each study group  Log-rank test reported for time-dependent data  Fischer’s exact test is reported for categorical variables  T-test between group comparisons corrected for multiple comparisons  Mann-Whitney U test used for continuous variables with non-normal distribution

13.  Primary Clonidne/DTO- median length was 27% shorter than for the placebo/DTO group  (11 days [95%CI: 8-15] vs 15 days [95% CI 13-17]) P=0.02  Secondary NO difference in weight loss Total dose of DTO for clonidine/DTO group was 19.4 ml (7.7 mg ME) vs 47.9 ml (19.2 mf ME) P<0.03 ANOVA  The divergence was seen at 5 days of treatment 3 infant in placebo group experienced seizures vs none in the clonidine group 7 infants in the clonidine group experienced rebound (increasing MFS requiring restart of DTO 12-48 hours after discontinueation  Dispite inclusion of these additional days of treatment, the median length of treatment was still less than the placebo group.  Blood pressure and heart rates were statistically lower in the clonidine group but remained in the normal range for newborns  No intervenstions were required

14.  Scheduled morpine…failed  scheduled morpine + clonidine

17. Background: clonidine is a potential benificial therapy for NAS due to safety profile, ease of administration, and lack of a requirement for tapering Study Design: retrospective Outcomes:

18. Methods  14 patients were identified  11 patients were treated with fentanyl for sedation and 3 were born unto opioid-dependent mothers  All treated with clonidine 0.5-1 mcg/kg orally every 6 hours  No patients received opioids  Stability of patients and NAS scores were assessed at 24-48 hours  NAS scoring system was done every 3 to 4 hours during pharmacologic intervention and every 48 hours after discontinuation of intervention  Vital signs and oxygen saturation were recorded hourly  No exclusion criteria

19. Results  Mean duration of treatment was 6.8 days (range 4-15)  Mean abstinence scores were 6.4 pretreatment (range 0-20) and 1.9 posttreatment (range 0-5)  No patient suffered from adverse events from clonidine

20.  Mean GA 30.1 weeks  Treatment started in 10 patients in anticipation of withdrawal and 4 after NAS scores were optained  Clonidine was stopped abruptly in 12 patients and tapered (by 0.25 mcg/kg every 6 hours) in 2 patients without adverse effects

21.  Opiates effect on nervous system  Clonidine protective effect of nervous system

22.  How do we d/c it?  Dose  Adverse effects to monitor

24.  Gauanfacine  Guanabenz  lofixidine

27. Angela Stein, Pharm.D. PGY-1 Pharmacy Resident St. Johns Mercy Medical Center St. Louis College of Pharmacy